Morbidity and mortality caused by bovine diarrhea virus (BDV) in dairy and beef herds is a worldwise unsolved economic problem. A subclinical form characterized by high morbidity and low mortality is endemic and is associated with diminished respiratory capacity, neonatal diarrhea, ulcerations in the digestive tract, immunodeficiency, and, in calf bearing bovines, abortion teratogenicity. The disease is recognizable in claves, but adult carriers are difficult to identify.
An acute form of the disease results from infection of the fetus in the first trimester of pregnancy. The course of this form of the disease is insidious. The claves may survive the first infection, but those that do become immunotolerant, and excrete live viruses. They cannot survive a second infection. Since their capacity as carriers cannot be detected by titration of their sera, these animals are responsible for spreading of the disease from herd to herd.
BDV also infects hog populations. In hogs, it is important to distinguish animals as being infected by either BDV or hog chlorea virus, since hog cholera is an economically important disease, while the bovine diarrhea infection is of transient significance, and could, for the most part, be ignored. Hogs infected with cholera must be slaughtered, and since present diagnostic methods in hogs cannot distinguish between these two types of infection, hogs which are, in fact, only infected with BDV must also be destroyed.
Present means of detection of BDV infection in claves are equally deficient, in that they rely on titration for antibodies in sera, which titration will fail to detect the immunotolerant calves. Thus, a diagnostic method is desired, but presently unavailable, which is capable both of detecting the presence of the virus in newborn animals with chronic infections, and in distinguishing between hog cholera virus and BDV infections. This could be accomplished either using antibodies with high affinity and specificity for the virus particles or using nucleic acid oligomeric probes capable of specific hybridization to the viral sequences.
Similarly, in addition to the need for improved diagnostics, there is, at present, no effective vaccine which is successful in preventing the spread of the disease caused by BDV. It is, of course, desirable that such a vaccine would confer long-term immunity, would not infect the fetus of the inoculated animal, and would have no undesirable side effects such as induction of immunotolerance to the virus, or depression of the immune system. These characteristics are difficult if not impossible to acquire in an attenuated or killed virus vaccine. Such vaccines, for the most part, constitute the present state of the art (Saurat, P., et al. 'La Maladie des Muqueuses" (1972) pp. 229-251, L'Expansion scientific francaise Paris). Recently, Fernelius, A. L., et al. (am J Vet Res (1971) 32:1963-1979) have reported a vaccine prepared from a high molecular weight soluble antigen obtained by density gradient centrifugation from BDV virus grown in embryonic bovine kidney cells.
The approaches used in the art for the detection of and protection against bovine viral diarrhea have been largely empirical and have not utilized refined knowledge of the nature of the vector causing the disease. The bovine diarrhea virus has, however, been classified, along with hog cholera and border disease viruses as a pestivirus which is a member of the family Togaviridae (Porterfield, J. S., "the Togavirions. Biology, Structure, Replication" Schlesinger, W., Ed. (1980), Academic Press, pp. 17-24).
By analogy to other togaviruses, these viruses should contain a capsid protein and two or three membrane glycoproteins (Horzinek, M.C., Non-arthropod borne Togaviruses (1981). Academic Press, London.) Epitopes which are capable of raising antibodies associated with neutralization and protection against infection are expected to be contained in the membrane proteins (e.g., see Boere, W., et al., J Virol (1984) 52:572-582). The pestiviruses are also characterized by soluble antigen that are approximately 80 kD proteins. A 76 kD protein from BDV has, in fact, been used as an experimental vaccine (Fernelius, A. L., et al. supra).